137 Interplay between host defenses and viral anti-defenses as a major factor of viral cytopathogenicity

The prevailing paradigm posits that virus-induced cellular injuries (cytopathic effect, CPE) are caused by hijacking of cellular substrates, energy, and infrastructure by the pathogens for the needs of their reproduction. However, this appears to be not the sole, and even not the most important, mechanism of cellular pathology triggered by viral infections. There is ground to believe that the most severe harm may come not from viral reproduction as such but rather from (miscalculated) host defenses as well as from viral anti-defensive activities. The experiments to be presented strongly support this notion. By using as a model system HeLa cells infected with mengovirus (a strain of encephalomyocarditis virus, a lytic picornavirus), we show that the major signs of CPE caused by this virus can be uncoupled from its reproduction. This can be achieved by partial mutual disarmament of the virus (by mutational inactivation of one of its anti-defensive “security” proteins, the leader protein) and the host (by chemical inhibition of one of its defensive innate immunity mechanisms, apoptosis). Under such conditions, the appearance of major cellular injuries is postponed until well after the completion of the viral reproduction. Remarkably, a more profound disarmament of the virus (by additional deletion of its second security protein, 2A) accompanied with a marked suppression of the viral reproduction leads to a faster death of the infected apoptosis-deficient cells due primarily to their defensive suicidal programmed necrosis. Thus, efficient strategies to ameliorate virus-induced injuries may include measures aimed at suppression of not only viral reproduction or viral anti-host functions but also of host defenses.